An understanding of the effect of ethanol on the hypothalamic- pituitary-adrenal axis (HPAA) requires an appreciation of the central and peripheral regulatory components which constitute the HPAA. Intimately involved in the regulation of the HPAA are hypothalamic- and possibly peripheral-derived corticotropin- releasing hormone (CRF) and pituitary-gland derived beta- endorphin (BE), which is cosecreted with ACTH. Specific binding sites for CRF and BE have been identified in various rat peripheral tissues and bovine chromaffin cells in culture. Occupancy of the CRF binding sites in rat adrenal membranes and bovine chromaffin cells of BE binding sites in hepatic membranes activate the adenylate cyclase/cAMP system. Furthermore, peripheral-tissue binding sites for CRF and BE appear to be modulated by glucocorticoids as to pituitary CRF binding sites. Follow-up experiments, in which rats were exposed to ethanol vapors for 14 days revealed reduced pituitary CRF binding and reduced CRF binding to a variety of CRF binding sites, including what was initially demonstrated to be reduced CRF erythrocyte (RBC) binding. These observations suggested that CRF binding to presumed RBC membranes and pituitary membranes may be modulated in a similar direction. Furthermore, it was reasoned that establishment of this concept would be an important contribution in the area of clinical neuroendocrinology.